1. Introduction and structural characteristics of EGCG

Gallocatechin gallate (Epigallocatechin Gallate, EGCG) is the predominant polyphenolic compound found in green tea, featuring the molecular formula C₂₂H₁₈O₁₁. Its structure comprises a benzene ring and multiple hydroxyl groups, demonstrating substantial antioxidant and anti-inflammatory properties. The antitumor efficacy of EGCG mainly arises from the multiple hydroxyl groups within its structure, which efficiently neutralize free radicals in the body, thereby safeguarding cells against oxidative damage [1].

1. The pathogenesis and preventive significance of colon cancer

Colorectal cancer (CRC) is a prevalent malignant tumor within the digestive system, exhibiting a rising trend in both incidence and mortality rates worldwide. The pathogenesis of colorectal cancer is intricate and multifaceted, encompassing genetic mutations, epigenetic alterations, inflammatory responses, and dysbalances in gut microbiota [2].In the context of genetic mutations, pivotal genes including APC, KRAS, and TP53 are instrumental in the progression of colorectal cancer;epigenetic changes, like DNA methylation and histone modifications, can influence cell proliferation and apoptosis by regulating gene expression; Chronic inflammatory responses, especially those stemming from dysbiosis of the gut microbiota, are deemed to be a major trigger for the onset of colorectal cancer.Therefore, finding highly effective and low-toxicity natural anti-tumor drugs has become a research hotspot. EGCG, as a green tea polyphenol compound, has gained widespread attention due to its significant antioxidant, anti-inflammatory, and anti-tumor activities.

1. The Function of EGCG in Inhibiting Colon Cancer

2. Mechanism for Inhibiting the Proliferation of Colon Cancer Cells

The inhibitory effect of EGCGs on the proliferation of colon cancer cells is primarily accomplished by modulating the cell growth cycle and signaling pathways[3]. Research has demonstrated that EGCG halts the cell cycle at the G1 phase, effectively inhibiting the proliferation of colon cancer cells.Specifically, EGCG is capable of downregulating the expression of cell cycle proteins, including Cyclin, as well as cyclin-dependent kinases (CDKs), such as Cyclin D1 and CDK4/6. This downregulation subsequently suppresses the phosphorylation of the retinoblastoma protein (pRb).This leads to the inhibition of E2F transcription factor activity, ultimately blocking the progression of the cell cycle [4]. For instance, in the colorectal cancer cell line HCT116, cells treated with EGCG demonstrate a significant G1 phase arrest, accompanied by a substantial reduction in the cell proliferation rate.

EGCG restrains the multiplication of colorectal cancer cells by modulating several signaling pathways. Among these, the PI3K-Akt signaling pathway stands out as a pivotal target for EGCG's action. This pathway is instrumental in regulating cell proliferation, survival, and apoptosis. EGCG can inhibit the activation of PI3K and the phosphorylation of Akt, thereby effectively blocking the downstream effects of this signaling pathway. For instance, in SW480 colon cancer cells, treatment with EGCG resulted in reduced phosphorylation levels of PI3K and Akt, along with a downregulation of mTOR activity, leading to a significant inhibition of cell proliferation[5].

1. Induce apoptosis and autophagy in colorectal cancer cells

The mechanism through which EGCG induces apoptosis in colorectal cancer cells entails the modulation of multiple signaling pathways.Studies have demonstrated that EGCG can initiate apoptosis signals via the mitochondrial pathway by elevating the Bax/Bcl-2 ratio, facilitating the release of cytochrome C, and subsequently triggering the Caspase-9 and Caspase-3 cascade reactions, ultimately resulting in cell apoptosis [6]^.EGCG further augments the susceptibility of colorectal cancer cells to apoptosis signals by modulating death receptor pathways, like the Fas/FasL signaling pathway.

EGCG has demonstrated substantial efficacy in inducing autophagy within colon cancer cells.Autophagy is a cellular degradation mechanism that involves the breakdown of damaged organelles or proteins through the formation of autophagosomes[7], thereby preserving cellular homeostasis.EGCG facilitates the formation and maturation of autophagosomes by enhancing the expression of autophagy-related genes like Beclin-1 and LC3, ultimately resulting in necroptotic death [8].Significantly, autophagy fulfills a dual function in tumor cells, acting both as a survival mechanism and as a catalyst for cell death. By modulating autophagy-related signaling pathways, including the PI3K/Akt/mTOR pathway, EGCG harmonizes the pro-survival and pro-death effects of autophagy, thereby accomplishing targeted elimination of colon cancer cells.

1. The Signaling Pathway of EGCG in Combating Colon Cancer

2. PI3 Regulation of the K/Akt Signaling Pathway

The PI3K/Akt signaling pathway is pivotal in numerous biological processes, including cell proliferation, apoptosis, and metabolism. In the progression of colorectal cancer, the aberrant activation of this pathway is widely acknowledged as a pivotal molecular mechanism.EGCG exerts an impact on the crucial nodes within the PI3K/Akt signaling pathway via multi-level regulatory actions, thereby restraining the proliferation of colorectal cancer cells and facilitating their apoptosis [6].

EGCG is capable of directly restraining the activity of PI3K. PI3K serves as an upstream kinase within the signaling pathway; upon its activation, the second messenger phosphatidylinositol (3,4,5)-triphosphate (PIP3) is generated, which subsequently activates Akt. Studies have demonstrated that EGCG obstructs the phosphorylation and activation of Akts by inhibiting the expression and activity of the PI3Ks catalytic subunit p110, consequently diminishing the production of PIP3 [5].For instance, in the colorectal cancer cell line SW480, treatment with EGCG markedly decreased the expression level of p110 and the phosphorylation level of Akt, thereby furnishing direct molecular evidence of EGCG's antitumor efficacy.

1. The Impact of the Ras/RAF/MEK/ERK Signaling Pathway

The Ras/RAF/MEK/ERK signaling pathway is a sophisticated cascade reaction system that encompasses the phosphorylation of numerous pivotal proteins. The Ras protein serves as an upstream signal molecule, initiating the activation of the RAF kinase. This activation subsequently triggers the MEK kinase, culminating in the phosphorylation and activation of the ERK kinase. Once activated, ERK migrates into the nucleus, where it modulates the expression of diverse genes, thereby influencing critical biological processes such as cell proliferation, differentiation, and apoptosis.

Research indicates that EGCG can markedly suppress the activation of the Ras/RAF/MEK/ERK pathway.Specifically, EGCG diminishes the expression of the Ras protein and reduces the phosphorylation levels of RAF, thereby inhibiting the activation of MEK and ERK[1].This process not only inhibits the transmission of the signaling pathway but also diminishes the activity of downstream effector molecules, such as the c-Myc protein.As a pivotal regulator of cell proliferation and survival, the expression levels of c-Myc are markedly elevated in colorectal cancer. By inhibiting c-Myc expression, EGCG effectively suppresses tumor cell proliferation and survival.

1. EGCG and colorectal cancer microenvironment

2. Impacts immune regulation

EGCG boosts the body's anti-tumor immune response by activating crucial signaling pathways within the innate immune system, like the cGAS-STING pathway [10]^. Studies have demonstrated that EGCG can prompt the release of DNA from tumor cells. This released DNA is subsequently recognized by cGAS, which activates the STING signaling pathway. This activation leads to an increased expression of type I interferon (IFNβ), thereby activating effector T cells and enhancing the anti-tumor immune response[11].EGCG also boosts the body's anti-tumor immune response by regulating the activity of immune cells, such as CD4+ and CD8+ T cells. Furthermore, EGCG can reconfigure the tumor microenvironment by modulating the levels of immune cytokines. This includes reducing the expression of immunosuppressive factors (e.g., TGF-β, IL-10) within the tumor microenvironment and enhancing the secretion of pro-inflammatory factors (such as IFN-γ, TNF-α). Consequently, this transition shifts the tumor microenvironment from an immunosuppressed state to an immunologically activated state.

1. Inhibit inflammatory response and oxidative stress

EGCG can efficiently suppress the release of diverse inflammatory cytokines, including TNF-α and IL-6. Research has demonstrated that EGCG can substantially decrease the expression levels of TNF-α and IL-6 by inhibiting the activation of the NF-κB signaling pathway[12], thereby mitigating the cascade effects of inflammatory responses[2]^. Additionally, EGCG excels in combating oxidative stress. By stimulating the activity of antioxidant enzymes such as superoxide dismutase (SOD) and glutathione peroxidase (GPx), EGCG fortifies the body's antioxidant defense mechanisms, thereby diminishing the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Furthermore, EGCG can directly neutralize free radicals, safeguarding cells against oxidative damage.

1. The synergistic impact of EGCG in conjunction with other anti-colorectal cancer therapies

2. The synergistic interaction with chemotherapy drugs

EGCG remarkably augments the curative impacts of chemotherapy drugs by restraining tumor cell proliferation and triggering apoptosis.Studies have demonstrated that EGCG can inhibit tumor cells in the G0/G1 phase by modulating cell cycle-associated proteins, including Cyclin-Dependent Kinases (CDKs) and Cyclins, thereby effectively suppressing cell proliferation [11].EGCG also triggers apoptosis-related pathways, like the mitochondrial pathway and the death receptor pathway, spurring the apoptosis of tumor cells. Furthermore, EGCG exhibits pronounced efficacy in suppressing tumor cell migration and invasion. It accomplishes this by downregulating the expression of matrix metalloproteinases (MMPs), thereby diminishing the degradation of the extracellular matrix and consequently inhibiting the migratory and invasive abilities of tumor cells.For instance, "Research Progress on the Anti-Lung Cancer Mechanism of Astragalus Polysaccharides" highlights that astragalus polysaccharides demonstrate substantial efficacy in treating lung cancer via analogous mechanisms, thereby offering theoretical backing for the utilization of EGCG in colon cancer treatment [12].

1. Synergistic Effects with Radiotherapy and Targeted Medications

EGCG possesses notable antioxidant and anti-inflammatory attributes, efficiently mitigating oxidative stress and inflammatory reactions induced by radiotherapy.Radiotherapy utilizes high-energy rays to destroy tumor cell DNA, but it also harms the surrounding normal tissues, resulting in cellular injury and inflammation. EGCG serves to eliminate free radicals, safeguarding normal cells from the adverse effects of radiotherapy, thus augmenting the overall tolerance and treatment effectiveness [13]. For instance, in an animal experiment, the colorectal cancer mice that received a combined treatment of EGCG and radiotherapy had considerably smaller tumor volumes in comparison to those treated with radiotherapy alone, and their survival rates were significantly prolonged [14].

EGCG shows distinct advantages in regulating cellular signaling pathways and is capable of creating synergistic effects with targeted drugs. Targeted therapy hinders the growth and spread of tumors by specifically restraining key signaling molecules within tumor cells.EGCG has been demonstrated to modulate numerous signaling pathways related to colon cancer, like the PI3K/Akt and Wnt/β-catenin pathways[14]. For instance, in the study titled "Mechanisms of PPGs Anti-Colorectal Cancer Effects Mediated by miR-29a-3p/FOXO3a," PPG restrains the proliferation and migration of colon cancer cells by regulating the miR-29a-3p/FOXO3a pathway. A comparable mechanism might also be present in EGCG[15]. When utilized in combination with targeted drugs, EGCG can impede survival and proliferation signals at multiple tiers, augmenting the therapeutic effectiveness.

1. Conclusions and Future Outlook

2. The Existing Research Deficiencies and Challenges

Despite extensive research highlighting the substantial potential of EGCG in combating colorectal cancer, numerous shortcomings and challenges persist.The precise molecular targets and signaling pathways involved in the anti-colorectal cancer mechanism of EGCG remain inadequately elucidated. While research has demonstrated that EGCG can inhibit tumor cell proliferation and induce apoptosis by modulating various signaling pathways, including PI3K/Akt and MAPK/ERK, these findings predominantly stem from in vitro cell experiments. The lack of thorough validation via in vivo studies renders the clinical application potential of EGCG indeterminate [14].Furthermore, the challenge of EGCG's bioavailability represents a significant obstacle in ongoing research.The metabolic pathway of EGCG within the body is intricate, characterized by low absorption rates and vulnerability to degradation by gut microbiota, thereby complicating the attainment of therapeutic efficacy at effective concentrations [15]. Consequently, enhancing EGCG's bioavailability and elucidating the correlation between dosage and efficacy have emerged as pivotal technical hurdles demanding resolution.

1. Future research directions are proposed

Future research into the mechanisms of EGCG's anti-colorectal cancer effects should concentrate on molecular mechanisms, combination therapies, pharmacokinetics, bioinformatics, and clinical trials. This comprehensive approach aims to systematically and profoundly elucidate its anti-tumor mechanisms, thereby enhancing its clinical application in the treatment of colorectal cancer.Through interdisciplinary integration, the aim is to develop novel strategies and methodologies for the treatment of colorectal cancer. The specific recommendations are outlined as follows:

1. Comprehensive exploration of the molecular mechanisms of EGCG: Elucidate its precise molecular targets and signaling pathways, and further validate its mechanisms of action in vivo.For instance, the miR-29a-3p/FOXO3a pathway has been verified to play a role in the anti-colorectal cancer effects of PPG, as documented in "Research on the Mechanism of PPG Anti-Colorectal Cancer Effects Mediated by miR-29a-3p/FOXO3a." Similarly, exploring whether EGCG also exerts its anticancer effects through the regulation of this pathway or other non-coding RNAs and their target genes will elucidate its molecular mechanisms[2].

1. Research on the Integrated Application of EGCG with Other Therapeutic Modalities: Investigate the synergistic effects of EGCG when combined with surgery, radiotherapy, chemotherapy, and targeted therapy, aiming to mitigate toxic side effects and enhance treatment efficacy. For example, by performing in vitro cell experiments and employing animal models,Validate the enhanced efficacy and reduced toxicity observed when EGCG is administered alongside chemotherapeutic agents, thereby providing a theoretical foundation for clinical combination therapy protocols.Enhancing the Bioavailability of EGCG: Through advanced drug formulations and the incorporation of nanotechnology techniques, elevate the bioavailability of EGCG and refine its dosing regimen for optimal efficacy.Systematic examination of EGCG's absorption, distribution, metabolism, and excretion in the body can streamline the optimization of its dosing regimen, thereby boosting therapeutic effectiveness[2].

1. Utilizing big data and bioinformatics analysis: By leveraging high-throughput sequencing, proteomics, and other advanced technologies, systematically examine the alterations in gene expression and protein profiles of colon cancer cells following EGCG treatment, aiming to uncover novel targets and underlying mechanisms.For instance, by utilizing bioinformatics analysis, we can identify differentially expressed genes in response to EGCG treatment. This method facilitates the further validation of their functions, potentially revealing novel anti-colorectal cancer mechanisms[4].Conducting Clinical Trials: Design rigorous clinical trials to assess the safety and efficacy of EGCG in colorectal cancer patients, establishing a solid foundation for its practical application. Although in vitro and animal experiments have preliminarily confirmed the antitumor activity of EGCG,Its therapeutic impact on human colorectal cancer remains to be validated through clinical trials[2].

Through the comprehensive exploration of the aforementioned research direction, it is anticipated to offer novel strategies and methodologies for the treatment of colon cancer, thereby advancing the clinical utilization of EGCG in the realm of anti-colon cancer therapy.

The authors declare that they have no conflict of interest

No funding sources

The study was approved by the 1 Lincoln University College,Malaysia.

1. Li et al; "Mechanisms of Resveratrol in Anti-Colon Cancer: A Review" 40.11 (2023) Pp61-63

2. Wu et al; "Apoptosis and Apoptotic Body: Disease Message and Therapeutic Target Potentials" 39.1 (2021) Pp1-2, doi https://doi.org/10.1042/BSR20181192

3. Macha et al; "Neglected and Underutilized Crops: Unveiling Potential for Cancer Drug Discovery" 1.1 (2025) Pp1-2, doi https://doi.org/10.1201/9781003477792

4. Deng et al; "The Role of EGCG in Regulating the Immune Response in Colon Cancer" 208.5 (2022) Pp1234-1245

5. Lin et al; "The Role of EGCG in Anti-Inflammatory and Antioxidant Mechanisms in Colon Cancer" 16.1 (2023) Pp1023-1034

6. Shi et al; "The Role of EGCG in Apoptosis and Autophagy in Colon Cancer Cells" 13.7 (2022) Pp654-665, doi https://doi.org/10.1038/s41419-022-05082-8

7. Herdiana et al; "Nanoparticle-Based Antioxidants in Stress Signaling and Programmed Cell Death in Breast Cancer Treatment" 28.14 (2023) Pp5305, doi https://doi.org/10.3390/molecules28145305

8. Wang et al; "The Role of EGCG in the PI3K/Akt Signaling Pathway in Colon Cancer" 2023.1 (2023) Pp1-12, doi https://doi.org/10.1155/2023/1234567

9. Yang et al; "Handbook of Therapeutic Biomarkers in Cancer" 1.1 (2013) Pp1-2, doi https://doi.org/10.1201/b15029

10. Juneja et al; "Green Tea Polyphenols: Nutraceuticals of Modern Life" 1.1 (2013) Pp1-2, doi https://doi.org/10.1201/b14878

11. Preedy et al; "Adipokines" 1.1 (2011) Pp1-2, doi https://doi.org/10.1201/b11036

12. Gan et al; "Absorption, Metabolism, Anti-Cancer Effect and Molecular Targets of Epigallocatechin Gallate (EGCG): An Updated Review" 58.6 (2018) Pp924-941, doi https://doi.org/10.1080/10408398.2016.1231168

13. Talib et al; "Targeting Cancer Hallmarks with Epigallocatechin Gallate (EGCG): Mechanistic Basis and Therapeutic Targets" 29.6 (2024) Pp1373, doi https://doi.org/10.3390/molecules29061373

14. Nag et al; "Rising Potentials of Epigallocatechin Gallate (EGCG) Loaded Lipid-Based Delivery Platforms for Breast Cancer" 6.8 (2024) Pp426, doi https://doi.org/10.1007/s42452-024-06087-4

15. Zhou et al; "EGCG-Enabled Deep Tumor Penetration of Phosphatase and Acidity Dual-Responsive Nanotherapeutics for Combinatory Therapy of Breast Cancer" 1.1 (2024) Pp2406245, doi https://doi.org/10.1002/smll.202406245